The autonomic nervous system is separated into the cholinergic and adrenergic nervous systems. Norepinephrine, the neurotransmitter of the adrenergic nervous system, exerts its activity by interaction with receptors (adrenoceptors) on the effector organs or on the nerve endings. The adrenoceptors are of two primary types: alpha and beta. Further, based upon the selectivity of the receptors for a series of agonists and antagonists, the alpha adrenoceptors are divided into alpha.sub.1 and alpha.sub.2 subtypes.
Alpha.sub.1 adrenoceptors are those positioned on the effector organ, thus alpha.sub.1 stimulation produces a pharmacologic effect. Alpha.sub.2 adrenoceptors first were discovered on alpha-adrenergic nerve endings. These prejunctional alpha.sub.2 adrenoceptors are involved in the regulation of neurotransmitter release through a negative feedback mechanism mediated by the neurotransmitter.
A large amount of experimental evidence now supports the view that there is a heterogeneous class of alpha receptors which mediates vasoconstriction in the vasculature of the pithed rat and pithed cat. (For a general review see Timmermans and Van Zwieten, J. Med. Chem., 25, 1389 (1982).) Experiments using selective agonists and antagonists of both alpha.sub.1 and alpha.sub.2 receptors demonstrated that in addition to the classical postjunctional alpha.sub.1 receptor, an additional postjunctional receptor was present which closely resembled the prejunctional alpha.sub.2 adrenoceptor which had been characterized in many systems. The concept of postjunctional alpha.sub.2 adrenoceptors mediating prazosin-resistant vasoconstriction therefore was proposed (Timmermans, et al., Naunyn-Schmedeberg's Arch. Pharmacol., 310, 189 (1979), Ruffolo, Pharm. Biochem. and Behav., 22, 827 (1985).) Additional evidence suggests that these receptors are located extra-synaptically, and are activated primarily by circulating catecholamines as opposed to neuronally released norepinephrine which primarily activates the alpha.sub.1 adrenoceptor (Yamaguchi and Kopin, J. Pharm. Exp. Ther., 214, 275 (1980)). It has now been discovered that the prazosin-insensitive postjunctional alpha.sub. 2 receptor is pharmacologically distinct from the prejunctional alpha.sub.2 receptor and hereafter this postjunctional, prazosin-insensitive receptor shall be referred to as the alpha.sub.3 adrenoceptor.
As one of the primary regulators of peripheral vascular tone, alpha adrenoceptors long have been the targets of efforts to develop effective antihypertensive agents. These efforts have resulted in several compounds that interact selectively with alpha.sub.1 or alpha.sub.2 receptors. Selective agonists include phenylephrine and methoxamine which preferentially activate alpha.sub.1 receptors; and clonidine, alpha-methylnorepinephrine, and tramazoline which selectively activate alpha.sub.2 receptors. Examples of selective alpha-adrenoceptor antagonists include prazosin which has high selectivity for alpha.sub.1 adrenoceptors; and the alpha.sub.2 -selective blockers yohimbine and rauwolscine. Absent from the therapeutic armamentarium are selectve agonists and antagonists of alpha.sub.3 vis-a-vis alpha.sub.2 adrenoceptors.
Based on the distribution and function of alpha.sub.3 adrenoceptors it is clear that compounds having selective affinity for alpha.sub.3 vis-a-vis alpha.sub.2 adrenoceptors (hereafter referred to as alpha.sub.3 selective) would be important additions to the agents available in treating cardiovascular disease. Alpha.sub.3 adrenoceptors have been found in spontaneously hypertensive rats (Medgett and Langer, J. Pharmacol. Exp. Ther, 231, 159 (1984)) and to play a role in the maintenance of blood pressure in essential hypertension (Bolli, et al., Journal of Hypertension, 1985. Prazosin-insensitive alpha-adrenergic (alpha.sub.3) contractile mechanisms also have been found on human digital arteries and veins. Stevens, M. J. and Moulds, R. F. W., J. Cardiovasc. Pharmacol, 4:S129-S133 (1982). In animals and man there is evidence for increased activation of alpha.sub.3 receptors in the hypertensive state. Because the alpha.sub.3 adrenoceptor is unaffected by the alpha.sub.1 antagonists presently available for clinical use, blockade of vasoconstriction mediated by circulating catecholamines which act on alpha.sub.3 receptors offers a novel approach to adrenolytic therapy in hypertension.
Further, reflex tachycardia is a frequent and severe adverse effect encountered when utilizing available alpha-adrenoceptor antagonists in the treatment of hypertension. This adverse effect is mediated by enhanced norepinephrine release by the nerves that innervate the cardiac pacing tissues which is a cumulative effect of the reduction in systemic blood pressure produced by alpha.sub.1 adrenoceptor blockade and the disruption of feedback inhibition of norepinephrine release resulting from alpha.sub.2 blockade. Thus, because selective alpha.sub.3 antagonists leave alpha.sub.2 adrenoceptors free to participate in feedback inhibition of norepinephrine release, antihypertensive therapy with these agents will be associated with a lesser incidence and lower frequency of tachycardia.
The cardiovascular diseases for which alpha.sub.3 selective antagonists are useful are not limited to hypertension. Alpha.sub.3 receptors are present on coronary arteries (Holtz, et al., Eur. J. Pharm., 82, 199 (1982)); as in the canine saphenous vein, the coronary artery alpha.sub.3 adrenoceptors may be innervated. Thus, an alpha.sub.3 -selective antagonist would be an effective coronary blood vessel dilator thereby increasing blood flow and alleviating symptoms of cardiac hypoxia such as angina pectoris. Additionally, blockade of alpha.sub.3 adrenoceptors, alone or in combination with alpha.sub.1 adrenoceptor blockade, also reduces cardiac preload and afterload thereby enhancing cardiac function in cardiomyopathic diseases such as congestive heart failure. In addition to agents employed in the treatment of cardiovascular diseases, alpha.sub.3 -selective antagonists will make possible further characterization of the adrenergic nervous system to enable identification of other disease states in which treatment with these agents will be of therapeutic benefit.
U.S. Pat. No. 4,469,634, dated Sept. 4, 1984, describes allyloxy- and allythio-2,3,4,5-tetrahydro-1H-3-benzazepines useful as intermediates for preparing alpha.sub.2 adrenoceptor affinity resins and as antihypertensive agents. Included in the compounds disclosed in this reference is 9-allyloxy-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. As is demonstrated below, despite its structural similarity to 9-(3-methyl-2-butenyloxy)-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3 benzazepine, an alpha.sub.3 selective antagonist of the present invention, the alpha.sub.3 selectivity of the reference compound does not approach the high degree of specificity exhibited by the presently invented compounds.